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The Forkhead Transcription Factor FoxO Regulates Transcription of p27Kip1 and Bim in Response to IL-2

Marie Stahl, Pascale F. Dijkers, Geert J. P. L. Kops, Susanne M. A. Lens, Paul J. Coffer, Boudewijn M. T. Burgering and René H. Medema
J Immunol May 15, 2002, 168 (10) 5024-5031; DOI: https://doi.org/10.4049/jimmunol.168.10.5024
Marie Stahl
*Department of Molecular Biology H8, Netherlands Cancer Institute, Amsterdam, The Netherlands; and
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Pascale F. Dijkers
†Department of Pulmonary Diseases and
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Geert J. P. L. Kops
‡Laboratory for Physiological Chemistry, University Medical Center, Utrecht, The Netherlands
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Susanne M. A. Lens
*Department of Molecular Biology H8, Netherlands Cancer Institute, Amsterdam, The Netherlands; and
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Paul J. Coffer
†Department of Pulmonary Diseases and
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Boudewijn M. T. Burgering
‡Laboratory for Physiological Chemistry, University Medical Center, Utrecht, The Netherlands
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René H. Medema
*Department of Molecular Biology H8, Netherlands Cancer Institute, Amsterdam, The Netherlands; and
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Abstract

The cytokine IL-2 plays a very important role in the proliferation and survival of activated T cells. These effects of IL-2 are dependent on signaling through the phosphatidylinositol 3-kinase (PI3K) pathway. We and others have shown that PI3K, through activation of protein kinase B/Akt, inhibits transcriptional activation by a number of forkhead transcription factors (FoxO1, FoxO3, and FoxO4). In this study we have investigated the role of these forkhead transcription factors in the IL-2-induced T cell proliferation and survival. We show that IL-2 regulates phosphorylation of FoxO3 in a PI3K-dependent fashion. Phosphorylation and inactivation of FoxO3 appears to play an important role in IL-2-mediated T cell survival, because mere activation of FoxO3 is sufficient to trigger apoptosis in T cells. Indeed, active FoxO3 can induce expression of IL-2-regulated genes, such as the cdk inhibitor p27Kip1 and the proapoptotic Bcl-2 family member Bim. Furthermore, we show that IL-2 triggers a rapid, PI3K-dependent, phosphorylation of FoxO1a in primary T cells. Thus, we propose that inactivation of FoxO transcription factors by IL-2 plays a critical role in T cell proliferation and survival.

  • Received February 6, 2002.
  • Accepted March 18, 2002.
  • Copyright © 2002 by The American Association of Immunologists
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The Journal of Immunology: 168 (10)
The Journal of Immunology
Vol. 168, Issue 10
15 May 2002
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The Forkhead Transcription Factor FoxO Regulates Transcription of p27Kip1 and Bim in Response to IL-2
Marie Stahl, Pascale F. Dijkers, Geert J. P. L. Kops, Susanne M. A. Lens, Paul J. Coffer, Boudewijn M. T. Burgering, René H. Medema
The Journal of Immunology May 15, 2002, 168 (10) 5024-5031; DOI: 10.4049/jimmunol.168.10.5024

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The Forkhead Transcription Factor FoxO Regulates Transcription of p27Kip1 and Bim in Response to IL-2
Marie Stahl, Pascale F. Dijkers, Geert J. P. L. Kops, Susanne M. A. Lens, Paul J. Coffer, Boudewijn M. T. Burgering, René H. Medema
The Journal of Immunology May 15, 2002, 168 (10) 5024-5031; DOI: 10.4049/jimmunol.168.10.5024
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